Abstract Prostate cancer is the most common cancer in men in North America and the second leading cause of cancer- related deaths in males. The high mortality rate of this disease is mainly due to the metastatic spread of malignant cells. Compelling evidence suggests that angiogenesis is a critical factor regulating the growth and spread of cancer. However, a significant gap exists in our understanding of the genes that impact these processes. Our preliminary data show that prostate cancer cell lines and tumors produce angiogenic CXC chemokines through a mechanism dependent on NF-:B activation. The angiogenic chemokines produced by these prostate cancer cells induce endothelial cell chemotaxis and this effect is dependent upon the angiogenic chemokine receptor CXCR2. Moreover, we also demonstrate that the Ron receptor tyrosine kinase is highly expressed in human prostate tumors and prostate cancer cell lines. In addition, we show that a blockade of Ron signaling in prostate cancer cells inhibits angiogenic CXC chemokine production and results in the stabilization of the NF-:B inhibitory protein I:B. Utilizing gene-targeted mice, we also show that a functional loss of Ron or CXCR2 significantly delays prostate tumor development in vivo. Based on our preliminary data, this proposal will test the central hypothesis that Ron signaling promotes prostate tumor growth by stimulating angiogenic chemokine production leading to CXCR2-mediated angiogenesis. The studies in this proposal will focus on the unique role of the Ron-chemokine axis in regulating prostate tumor growth by (i) delineating the mechanisms responsible for the Ron-dependent regulation of angiogenic chemokine production, (ii) determining the impact of Ron signaling in prostate tumor growth in vivo, and (iii) by examining the functional significance of the chemokine receptor, CXCR2, in prostate tumor growth and angiogenesis. In total, we hope to understand role of the novel Ron-chemokine axis in the development and spread of prostate cancer and provide a scientific rationale for new diagnostic or treatment modalities for this disease. PUBLIC HEALTH RELEVANCE: Prostate cancer is the most common cancer and is the second leading cause of cancer in men. Approximately 200,000 new cases of prostate cancer will be diagnosed and about 40,000 men are estimated to die of this disease. The prevalence and morbidity of prostate cancer are likely to increase with the aging population and the Veteran's Administration's expenditures and care for patients with this disease will increase accordingly. While significant effort and advancement into the treatment of this disease have occurred at the VA and other institutions, a significant gap still exists in our knowledge of new treatment options for patients with prostate cancer. In our laboratory, we have exciting new data which suggests a novel protein, termed Ron, may be involved in prostate tumor formation and growth. Ron is a protein that resides on the surface of cells. The function of Ron is to transmit signals from outside the cell into intracellular messages. Ron is classified as a receptor tyrosine kinase and many of these families of proteins are overproduced in various cancer. The overproduction of Ron leads to the activation of several signaling pathways inside the cell that promote cell growth. In order for a tumor to grow and metastasize (or spread to other parts of the body), the tumor must recruit it's own blood supply. The process of forming new blood vessels is called angiogenesis. Tumor cells, and in particular prostate cancer cells, secret small molecules, such as angiogenic chemokines, that are important for angiogenesis because they attract blood vessels to come to the growing tumor. Angiogenesis is vital for tumor cells to maintain a constant supply of nutrients and oxygen, and to get rid of waste. Without angiogenesis, the tumor cells will never spread to other organs in the body and the tumor would be limited in growth. Prostate cancer cells produce angiogenic chemokines and metastasize and it is therefore important to understand how this process is regulated. Our very recent data show that Ron is overproduced in human prostate cancer and that Ron is a key factor that promotes the production of angiogenic chemokines from prostate cancer cells. Based on our research, we propose that Ron is a promising and novel protein to study in prostate cancer, and we suggest that Ron can stimulate prostate tumor growth and metastasis by stimulating angiogenesis. The studies in this proposal will define the importance of the high levels of Ron in prostate cancer and will determine if blocking Ron will lessen the ability of prostate tumor cells to grow and recruit blood vessels. The proposed studies are very important in furthering our understanding of prostate cancer and potential treatment options. Apart from our nascent studies, nothing is known about Ron in prostate cancer or Ron and the regulation of angiogenic chemokines. With the funding of this application, we will perform the first detailed studies of Ron as a potential target in prostate cancer. My laboratory is dedicated to prostate cancer research and we have all of the necessary expertise and equipment to complete the studies in this proposal. Moreover, we are very excited about the potential of Ron to be a clinically relevant therapeutic target in this disease.